The proposed study is resubmitted for work to further develop the research of the applicant into the effects of cumulative lead exposure on the pathogenesis of several chronic diseases. This work, to date, has included development of an x-ray fluorescence (K-XRF) technique to measure bone lead levels in over one-thousand men and women participating in long-running cohort studies, the NAS and the NHS. Preliminary research findings include the cross-sectional relationship between bone lead and an increased odds of the occurrence of hypertension, and, in pilot studies, of decreased creatinine clearance and decreased performance on cognitive testing. The current application proposes to continue the studies of lead and health in these two cohorts, modifying epidemiologic design, data collection, and sample analysis to fully test hypotheses regarding the cross-sectional relationship of lead dose to kidney function, cognitive performance, and serum uric acid. Additionally, hypotheses regarding the modification of bone lead toxicity by markers of bone resorption will be tested. This should help to distinguish between "bone lead as a proxy of cumulative absorption" and "bone lead mobilization" as a mechanism explaining the role of bone lead as a biomarker of chronic lead toxicity. If the first mechanism predominates, bone lead is serving as a proxy for cumulative exposure and effects elsewhere in the body, but by itself is of less biological importance. If the second mechanism dominates, it would then be important to examine factors that influence bone lead, with important implications for the development of possible strategies for secondary prevention of toxicity from bone lead.